CLL/SLL,   MCL,  MZL,  FL

CAR-T therapy with or without conditioning chemotherapy: Results from a phase I trial

On 2 April 2019, Mark Geyer and colleagues from the Memorial Sloan Kettering Cancer Center, New York, NY, USA, published in JCI Insight the results of a phase I trial. This study investigated the safety and long-term follow-up of chimeric antigen receptor T-cell (CAR-T) therapy with or without conditioning chemotherapy in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) or indolent B-cell non-Hodgkin lymphoma (B-NHL).

CAR-T therapy has shown great promise for the treatment of patients with R/R CLL or B-cell NHL who cannot be cured with standard of care regimens and who constitute a great unmet medical need. In this single-center, non-blinded, phase I trial (NCT00466531), the investigators sought to evaluate the efficacy and toxicity their CAR-T construct with or without conditioning chemotherapy.

Study design & baseline characteristics
  • N = 20 patients included in this analysis:
    • R/R CLL: n = 16 patients
    • R/R B-NHL: n = 4 patients
      • Marginal zone lymphoma (MZL): n = 2
      • Follicular lymphoma (FL): n = 1
      • Mantle cell lymphoma (MCL): n = 1
    • Male patients: 70%
    • Median age (range): 63 (43−75) years
    • Median number of prior lines (range):
      • CLL cohort: 4 (1−11)
      • B-NHL cohort: 8 (6−10)
    • Molecular and cytogenetic abnormalities in the CLL cohort:

Unmutated immunoglobulin heavy-chain variable region gene (IgHV)

n = 9

11q deletion

n = 5

17p deletion or TP53 loss

n = 4

Complex karyotype

n = 3

  • CAR-T construct & infusion:
    • CD28 co-stimulatory domain: 19−28z
    • Median duration of autologous T-cell collection (range) prior CAR-T infusion:
      • CLL cohort: 38 (20−225) days
      • B-NHL cohort: 109 (68−139) days
    • Median CD4+:CD8+ ratio in collected autologous T-cells (range):
      • CLL cohort: 1.9:1 (0.3:1−5:1)
      • B-NHL cohort: 1.9:1 (0.9:1−13.2:1)
    • Median CD4+:CD8+ ratio in infused CAR-T cells (range):
      • CLL cohort: 5.7:1 (0.3:1−0:1)
      • B-NHL cohort: 1.8:1 (0.8:1−3.1:1)
    • Median transduction efficiency (range): 30% (22−59%)
    • Median CAR-T cell product manufacturing (range) for entire cohort: 15 (11−19) days
  • Study treatment stages for CLL cohort. The B-NHL cohort followed treatment Stage 3 only:
  • Stage 1 (n = 3):
    • CAR-T infusion dose: 1.2−0 x 107 cells/kg
    • Conditioning chemotherapy: none
  • Stage 2A (n = 1 patient):
    • CAR-T infusion dose: 3.0 x 107 cells/kg
    • Conditioning chemotherapy: 1.5 g/m2 cyclophosphamide (Cy)
    • Outcome: this one patient died 48 hours after CAR-T infusion. This protocol was not used again
  • Stage 2B (n = 3):
    • CAR-T infusion dose: 0.40−0 x 107 cells/kg (split dose: 1/3 was administered on Day 0 and the rest on Day 1)
    • Conditioning chemotherapy: 1.5 g/m2 Cy
  • Stage 3 (n = 9):
    • CAR-T infusion total dose: 3.0 x 107 cells/kg (split dose as above)
    • Conditioning chemotherapy: Investigator’s choice:
      • Cy (0.3, 3 or 1.5 g/m2)
      • Fludarabine (Flu; 25 mg/m2) and Cy (1.5 g/m2)
      • Bendamustine (70 or 90 mg/m2)
    • Five patients in the CLL cohort were allowed to receive continuous ibrutinib treatment up to CAR-T infusion (median: 7 months) and four patients up to leukapheresis (median: 4.8 months)
Key findings

 

CLL cohort      (n = 16)

B-NHL cohort (n = 4)

Median follow-up (range)

40.6 (1.8−79.8) months

-

Median event-free survival

3.1 months

33.4 months

Median overall survival

17.1 months

Not reached

Objective response

38%

-

Complete response (CR) by IWCLL or Lugano criteria, respectively

n = 3/12

(two were MRD negative)

n = 2

(these patients were in CR at the time of CAR-T infusion and remained in CR thereafter)

Stable disease by IWCLL or Lugano criteria, respectively

n = 9

n = 2

Patients remaining in CR at median follow-up of 53 months or 24.7 months, respectively

100% (3/3)

50%

(the other patient died 27 months post-infusion due to lymphoma unrelated causes)

  • Amongst the patients with CLL, who did not achieve CR (n = 12):
    • Lost to follow-up: n = 1 patient
    • Died in active follow-up due to disease progression: n = 8 patients
    • Remained alive in active follow-up and received alternative treatment: n = 3 patients
      • Ibrutinib: n = 1
      • Allogeneic stem cell transplantation: n = 1
      • Other investigational therapy: n = 1
    • Amongst the patients with B-NHL who did not achieve CR (n = 2):
      • Patients achieving stable disease (SD): n = 2
    • Ex vivo expansion of T-cells (P = 0.040) and CD4+:CD8+ CAR-T cell ratios were significantly greater in patients receiving ibrutinib on leukapheresis
Safety

Cytokine release syndrome (CRS)

  • CRS was observed in all patients
  • The second fraction of CAR-T cells was withheld in 6 out of 11 patients with CLL (for whom split-dose infusion had been planned) due to early CRS development (including 4 out of 5 patients who were receiving concomitant ibrutinib)
  • CRS severity (total cohort):
    • Grade 1: n = 8 patients
    • Grade 2: n = 10 patients
    • Grade 3: n = 1 patient
    • Grade 5: n = 1 patient died 48 hours after CAR-T infusion (suspected sepsis syndrome)
  • Median CRS onset (total cohort): Day 1 post-infusion
  • Latest CRS onset (total cohort): Day 3 post-infusion
  • Median CRS duration (range): 2 (1−9) days
  • Patients receiving tocilizumab for CRS management: n = 3

Neurological toxicity (NT)

  • NT was observed in:
    • CLL cohort: n = 6
    • B-NHL cohort: n = 3
  • Patients receiving corticosteroids for NT management: n = 2
  • Median NT onset (total cohort): Day 2 post-infusion
  • Latest NT onset (total cohort): Day 11 post-infusion
  • Median NT duration (range): 1 (1−61) days
  • NT severity:
    • Grade 3 encephalopathy: n = 2 patients (reversible)
    • Prolonged encephalopathy and dysphasia: n = 1 (gradual improvement to baseline)
    • All other neurological events were considered as Grade 1 or 2 and were reversible:
      • Encephalopathy: n = 5
      • Dysphasia: n = 3
      • Dysarthria: n = 1
      • Hallucinations: n = 1

Other adverse events (AEs)

  • Common Grade 3−5 AEs observed in the total cohort:
    • Neutropenia: n = 8
    • Anemia: n = 6
    • Febrile neutropenia: n = 6
    • Thrombocytopenia: n = 5
    • Hypophosphatemia: n = 5
    • Lymphopenia: n = 4
    • Leukopenia: n = 4
    • Hypotension: n = 4
    • Hyperglycemia: n = 4
    • Hyponatremia: n = 4
Conclusions
  • All conditioning chemotherapy regimens tested and the 19-28z CAR-T infusions were acceptably tolerated by patients with R/R CLL and indolent B-NHL, with a few patients achieving a durable CR (CLL cohort only)
  • Since ex vivo T-cell expansion and CD4+:CD8+ CAR-T cell ratios were significantly greater in patients receiving ibrutinib on leukapheresis the authors suggested that ibrutinib may modulate autologous T-cell phenotype
References
  1. Geyer M.B. et al. Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL. JCI Insight. 2019 Apr 2;5. pii: 122627. DOI: 10.1172/jci.insight.122627.
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